The development of certain subtypes of breast cancer (BrCA) in postmenopausal women is largely influenced by non-genetic factors such as high fat diet (HFD)-induced obesity. The pathophysiological mechanisms that link obesity to BrCA risk include inflammatory processes; adipose tissue macrophages (ATMs) are a primary source of inflammation, however, there has been little mechanistic evaluation of their specific role in BrCA. There is evidence to confirm a regulatory role of miRNA-155 on M-induced inflammation; it has been shown that miRNA-155 directly inhibits suppressor of cytokine signaling 1 (SOCS1) in Ms, thus increasing their inflammatory potential. While it is clear that miRNA-155 can positively regulate M-induced inflammation, there is a fundamental gap in the understanding of its role on the regulation of ATM-induced inflammation in HFD enhanced BrCA. The long-term goal is to understand the role of ATMs in HFD enhanced BrCA that will lead to the development of behavioral and or medical treatments that are clinically relevant. The objective of this particular investigation is to determine the role of ATMs on inflammation and subsequent progression of HFD enhanced BrCA, and further, to evaluate if this process is regulated by miRNA-155. The central hypothesis is that the regulation of ATM-induced inflammation in HFD-enhanced BrCA is mediated through miRNA-155. The rationale for the proposed research is that elucidating the molecular mechanisms linking obesity to BrCA will translate to a more effective prevention/treatment approach. This hypothesis will be tested by pursuing two specific aims: 1) Determine the role of ATMs on inflammation and subsequent progression of BrCA; and 2) Evaluate the role of miRNA-155 on regulation of ATM-induced inflammation in BrCA. Under the first aim we will examine the effect of a HFD that closely mimics the standard American diet on BrCA progression in the PyMT mouse model of BrCA, and will examine the association between BrCA, adipose tissue inflammation, M polarization, and expression of miRNA-155. Further, using adoptive transfer of ATMs from wild-type mice fed a HFD to BrCA mice fed a low fat diet (LFD) we will directly determine the role of ATMs on progression of BrCA. In the second aim, we will test the hypothesis that miRNA-155 plays a critical role in the regulation of M-induced inflammation in HFD enhanced BrCA. To this end, using a PyMT X miRNA-155-/- mouse we will examine the role of miRNA-155 on ATM-induced inflammation and subsequent tumorigenesis. Further, using adoptive transfer of ATMs from HFD miRNA-155-/- mice to PyMT mice that will be fed a LFD we will determine if the effects of ATMs on BrCA progression are mediated through miRNA-155. The innovation of this investigation is anchored in the examination of the role of ATMs in BrCA, and further, the regulation of these Ms by miRNA-155. The proposed investigation is significant as it addresses prevention of incidence and progression of HFD-enhanced BrCA. If this hypothesis is correct miRNA-155 may be an important therapeutic target of ATM-induced inflammation in HFD-enhanced BrCA.